Perioperative acute kidney injury (AKI) following major cardiovascular surgery remains a significant problem. Perioperative AKI presents a challenging medical problem occurring in up to 30% of all cardiovascular procedures. The importance of postoperative renal dysfunction comes not only from the acute functional impairment of an organ critical to maintaining the internal environment, but also from its consistent association with increased rates of in-hospital mortality, even after adjustment for other contributing factors. In the setting of deep hypothermic circulatory arrest (DHCA), the incidence ranges as high as 8% to 50% (see, e.g., Augoustides et al. (2005) J. Cardiothorac. Vasc. Anesth. 19:446-452). AKI leads to increased postoperative morbidity and mortality, and in patients requiring renal replacement therapy the mortality rate is as high as 64%. However, despite several small “proof-of-concept” clinical studies, to date, there is no promising therapy available for prevention and/or treatment of cardiac surgery-associated AKI. Evidence is cumulating that potential mechanisms are associated with renal inflammation and ischemia-reperfusion (I/R) triggered by cardiopulmonary bypass (CPB) and DHCA.
Annexin A1 (ANXA1), a 37 kDa protein, is a member of the annexin superfamily, which consists of 13 calcium and phospholipid binding proteins with a significant degree of biological and structural homology (40-60%). ANXA1, originally identified as a mediator of the anti-inflammatory affects of glucocorticoids, has diverse biological functions including the regulation of inflammatory pathways, cell proliferation machinery, cell death signaling, and the process of carcinogenesis. Altering the expression or the localization of this protein can contribute to the pathogenesis of human diseases including inflammatory diseases, cardiovascular diseases, and cancer. It has been demonstrated that ANXA1 reduces the leukocyte-dependent myocardial damage associated with myocardial I/R injury (La et al. (2001) FASEB J. 15(12):2247-2256). The functional link between migrated leukocytes and the myocardial damage was confirmed, and significantly lower numbers of extravasated leukocytes were counted in the group of rats treated with ANXA1 (La et al., supra). Pharmacological analysis has demonstrated that the first 25 amino acids of the N-terminus of ANXA1 (termed Ac2-26, Ac: aceyl) is the active region of biological function and can reproduce the anti-inflammatory actions of the full-length protein (Gasterdelo et al. (2009) Am. J Pathol. 174(1):177-183). Ac2-26 protects against splanchnic artery occlusion and reperfusion injury by affecting neutrophil migration and against experimental myocardial ischemia-reperfusion by attenuating neutrophil migration (Gasterdelo et al., supra). The role of the endogenous anti-inflammatory mediator ANXA1 in controlling PMN trafficking and activation was addressed using the ANXA1 null mouse. Such findings suggest ANXA1 is a novel anti-inflammatory agent with a potential for the treatment of cardiovascular pathologies associated with neutrophil activation and recruitment. More recently, it has been demonstrated for the first time that ANXA1 N-terminus peptides derived from the N-terminal domain of ANXA1 possess strong anti-inflammatory properties by inhibiting NF-κB activity in human colon and pancreatic cancer cell lines, and in vivo anti-tumorigenesis properties in mice (See, e.g., PCT Publication No. WO/2008/121881).
The present invention provides compositions comprising ANXA1, and methods of using such compositions, for example, for perioperative renoprotection.